Dopaminergicneuronsoriginatingfromtheventraltegmentalarea(VTA)regulateavarietyofrewardanddrug- relatedbehaviors.However,upto20%ofVTAneuronsareGABAergicinterneurons,and~5%areGABA projectionneurons(GPNs)thatsendprojectionstoseveralbrainregionsinvolvedindrugreward,includingthe nucleusaccumbens(NAc).RecentlytheroleofVTAGABAneuronsandGPNsinreinforcementhasbeen exploredusingtransgenicmicethatallowforselectivemanipulationofVTAGABAneurons.However,therole oftheseGABAergicneuronsindrug-relatedbehaviorsismuchlessunderstood.Weproposetouseanovel combinatorialadeno-associatedviral(AAV)vectorsystemtotargetgeneexpressiontoeitherVTAGABA neuronsorVTA?NAccoreGPNsinwildtyperatsthathavebeentrainedtoself-administercocaine.The targetedGABAneuronswillexpressDREADDs(designerreceptorsexclusivelyactivatedbydesignerdrugs) whichwillallowustoselectivelystimulatetheseneuronalsubtypesduringextinctionofcocaineself- administration,andreinstatementofcocaine-seekingbehavior,aratmodelofrelapse.Wehypothesizethat VTAGABAneuronswillenhancerespondingduringextinctionlearningandcocaine-andcue-induced reinstatementbydisruptinglearnedcue-rewardassociations.Furthermore,webelievethatVTA?NAccore GPNactivationwillselectivelyenhancecue-inducedreinstatement,buthavelittleinfluenceoncocaine-induced reinstatementorextinction.Inaim1ofthisproposal,wewilldeterminetheroleofVTAGABAneuronsin extinctionlearningandreinstatementofcocaine-seeking.Wewillalsoundertakeapilotstudyinfemaleratsto determineifsexdifferencesexist.Inaim2wewillselectivelytargettheVTAGPNsprojectingtotheNAccore. Bycontrastingtheseresultsofaim1and2,wewilldetermineiftheVTA?NAccoreGPNeffectsdiffer substantiallyfromstimulatingallVTAGABAneurons,andwhetherthesespecificprojectionsalonemayserve asapotentialtargetfortherapeuticintervention.TheseexperimentswillestablishtheroleofVTAGABA neuronsindrug-seekingbehaviors,andwillprovidethenecessarygroundworkforfutureexplorationintothe mechanismsunderlyingVTAGABAneuroneffectsonrespondingtodrugcuesandtheprocessesunderlying relapse.